Abstract
The intracellular events involved in normal pancreatic growth have been extensively investigated in response to cholecystokinin. Recent data indicate that tyrosine kinase, phospholipase D, phosphatidylinositol 3-kinase, and p42/p44 MAPK are stimulated in rat pancreatic acinar cells. Although we begin to understand the intracellular signaling pathways activated in normal pancreas, such information is not yet available in pancreatic cancer cells. This study was undertaken to identify the growth factors and hormones involved in cell proliferation of two human pancreatic cancer cell lines of ductal origin, the MIA PaCa-2, and PANC-1 cells, and to establish the intracellular events involved in the control of their growth. We demonstrated that FGF-2, IGF-1, cerulein, and gastrin but not FGF-1, HGF, secretin, and PACAP, stimulated proliferation of MIA PaCa-2 and PANC-1 cells. Autocrine factors such as gastrin and IGF-1 were also responsible for their proliferation. In response to EGF, FGF-2, IGF-1, cerulein, gastrin and bombesin, tyrosine kinase, and tyrosine phosphatase activities were stimulated in both cell lines. The close relationship established between cell growth and tyrosine kinase activation results from the observation that maximal growth stimulation paralleled with maximal enzyme activation and that genistein, the tyrosine kinase inhibitor, blocked cell growth and enzyme activation. The implication of PLD in growth-stimulated processes is doubtful since all growth factors and hormones tested failed to stimulate an already very active PLD activity. We finally observed a constitutive activity of p44 MAPK in both cell lines and of p42 in MIA PaCa-2 cells. However, p38 and p42 were stimulated in MIA PaCa-2 and PANC-1 cells, respectively, by all growth factors and hormones.
Similar content being viewed by others
References
Upp, J. R., Poston, G. J., Machellan, D. G., Townsend, C. M., Barranco, C. S., and Thompson, J. C. (1988). Pancreas 3, 193–198.
Dembinski, A. B. and Johnson, L. R. (1980). Endocrinology 106, 323–328.
Barrowman, J. A. and Mayston, P. D. (1973). J. Physiol. 238, 73P-75P.
Solomom, T. E., Vanier, M., and Morisset, J. (1983). Am. J. Physiol. 245, G99-G105.
Dembinski, A. B., Gregory, H., Konturek, S. J., and Polanski, M. (1982). J. Physiol. 325, 35–42.
Rivard, N., Rydzewska, G., Lods, J. S., Martinez, J., and Morisset, J. (1994). Am. J. Physiol. 266, G62-G70.
Rivard, N., Rydzewska, G., Lods, J. S., and Morisset, J. (1995). Am. J. Physiol. 269, G352-G362.
Rivard, N., Rydzewska, G., Boucher, C., Lods, J. S., Calvo, E., and Morisset, J. (1994). Endocr. J. 2, 393–401.
Duan, R. D. and Williams, J. A. (1994). Am. J. Physiol. 267, G401-G408.
Seger, R. and Krebs, E. G. (1995). FASEB J. 9, 726–735.
Duan, R. D., Zheng, C. F., Guan, R. L., and Williams, J. A. (1995). Am. J. Physiol. 268, G1060-G1065.
Lierh, R. M., Melnykovych, G., and Solomon, T. E. (1990). Gastroenterology 98, 1666–1674.
Smith, J. P., Kramer, S. T., and Solomon, T. E. (1991). Regul. Pep. 32, 341–349.
Heald, E. B., Kramer, S. T., and Smith, J. P. (1992). Pancreas 7, 530–535.
Detjen, K., Fenrich, M. C., and Logsdon, C. D. (1997). Gastroenterology 112, 952–959.
Douziech, N., Calvo, E., Lainé, J., and Morisset, J (1998). Gastroenterology 114, A454 (abstract).
Mizuno, K., Takehara, N., and Nakamura, T. (1992). Biochem. Biophys. Res. Comm. 189, 1631–1638.
Ohmura, E., Okada, M.., Onoda, N., Kamiya, Y., Murakami, H., and Shizumi, K. (1990). Cancer Res. 50, 103–107.
Hamory, M. W., Verderame, M. F., Zagon, I. S., and Smith, J. P. (1997). Gastroenterology 112, A447.
Wong, L. and Johnson, G. R. (1996). J. Biol. Chem. 271, 20,981–20,984.
Byon, J. C. H., Kenner, K. A., Kusari, A. B., and Kusari, J. (1997). PSEBM 216, 1–20.
Yu, Z., Su, L., Hoglinger, O., Jaramillo, M. L., Banville, D., and Shen, S. H. (1998). J. Biol. Chem. 273, 3687–3694.
Lopez, F., Estève, J. P., Buscail, L., Deslesque, N., Saint-Laurent, N., Théveniault, M., et al. (1997). J. Biol. Chem. 272, 24,448–24,454.
Knauss, T. C., Jaffer, F. E., and Abboud, H. E. (1990). J. Biol. Chem. 265, 14,457–14,463.
Fukami, K. and Takenawa, T. (1992). J. Biol. Chem. 267, 10,988–10,993.
Billah, M. M. and Anthes J. C. (1990). Biochem J. 269, 281–291.
Kanfer, J. N. (1980). Can. J. Biochem. 58, 1370–1380.
Sarfati, P., Seva, C., Scemama, L., Pradayrol, L., and Vaysse, N. (1992). Pancreas 7, 657–663.
Hoshi, H. and Logsdon, C. D. (1993). Biochem. Biophys. Res. Commun. 196, 1202–1207.
Esch, F. Baird, A., Ling, N., Ueno, N., Hill, F., Denoroy, L., et al. (1985). Proc. Natl. Acad. Sci. USA 82, 6507–6584.
Neufeld, G. and Gospodarowicz, D. (1986). J. Biol. Chem. 261, 5631–5637.
Kaufmann, R., Schafberg, H., Rudroff, C., Henklein, P., and Nowak, G. (1997). Neuropeptides 31, 573–583.
Buscail, L., Cambillau, C., Seva, C., Scemama, J. L., De Neef, P., Robberecht, P., et al. (1992). Gastroenterology 103, 1002–1008.
Morisset, J., Douziech, N., Rydwewska, G., Buscail, L., and Rivard, N. (1995). Cell. Signalling 7, 195–205.
Vila, M. R., Nakamura, T., and Real, F. X. (1995). Lab. Invest. 73, 409–418.
Calvo, E., Boucher, C., Pelletier, G., and Morisset, J. (1996). Biochem. Biophys. Res. Commun. 229, 257–263.
Kiehne, K., Herzig, K. H., and Folsh, U. R. (1996). Pancreas 15, 35–40.
Rivard, N., McKenzie, F. R., Brondello, J. M., and Pouyssegur, J. (1995). J. Biol. Chem. 270, 11,017–11,024.
Bennett, A. M., Tang, T. L., Sugimoto, S., Walsh, C. T., and Neel, B. G. (1994). Proc. Natl. Acad. Sci. USA 91, 7335–7339.
Zhao, Z., Tan, Z., Wright, J. H., Diltz, C. D., Shen, S. H., Krebs, E. G., et al. (1995). J. Biol. Chem. 270, 11,765–11,769.
Rydzewska, G. and Morisset, J. (1995). Pancreas 10, 59–65.
Lacal, J. C. Moscat, J., and Aaronson, S. A. (1987). Nature (Lond.) 330, 269–272.
Plevin, R., Cook, S. J., Palmer, S., and Wakelam, M. J. O. (1991). Biochem. J. 279, 559–565.
Carnero, A., Cuadrado, A., Del Peso, L., and Lacal, J. C. (1994). Oncogene 9, 1387–1395.
Jiang, H., Luo, J. Q., Urano, T., Frankel, P., Lu, Z., Foster, D. A., et al. (1995). Nature (Lond.) 378, 409–412.
Aoki, K., Yoshida, T., Matsumoto, N., Ide, H., Sugimura, T., and Terada, M. (1997). Mol. Carcinog. 20, 251–258.
Dabrowski, A., Detjen, K. M., Logsdon, C. D., and Williams, J. A. (1997). Digestion 58, 361–367.
Crawley, J. B., Rawlinson, L., Lali, F. V., Page, T. H., Saklatvala, J., and Foxwell, B. M. J. (1997). J. Biol. Chem. 272, 15,023–15,027.
Cohen, P. S., Schmidtmayerova, H., Dennis, J., Dubrovsky, L., Sherry, B., Wang, H., et al. (1997). Mol. Med. 3, 339–346.
Dieckgraefe, B. K., Weems, D. M., Santoro, S. A., and Alpers, D. H. (1997). Biochem. Biophys. Res. Commun. 233, 389–394.
Schafer, C., Dabrowski, A., and Williams, J. A. (1997). Gastroenterology 112, A478.
Chomczynski, P. and Sacchi, N. (1987). Anal. Biochem. 162, 156–159.
Sambrook, J., Fritsch, E. F., and Maniatis, T. (1989). In: Molecular Cloning 2nd ed., Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 739–752.
Peikin, S. R., Rothman, A. J., Batzri, S., and Gardner, D. J. (1978). Am. J. Physiol. 235, E743-E749.
Bradford, M. A. (1976). Anal. Biochem. 72, 248–254.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Douziech, N., Lajas, A., Coulombe, Z. et al. Growth effects of regulatory peptides and intracellular signaling routes in human pancreatic cancer cell lines. Endocr 9, 171–183 (1998). https://doi.org/10.1385/ENDO:9:2:171
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/ENDO:9:2:171